Copy number variations and constitutional chromothripsis (Review)

Abstract

Both copy number variations (CNVs) and chromothripsis are phenomena that involve complex genomic rearrangements. Chromothripsis results in CNVs and other structural changes. CNVs are frequently observed in the human genome. Studies on CNVs have been increasing exponentially; the Database of Genomic Variants shows an increase in the number of data published on structural variations added to the database in the last 15 years. CNVs may be a result of replicative and non-replicative mechanisms, and are hypothesized to serve important roles in human health and disease. Chromothripsis is a phenomena of chromosomal rearrangement following chromosomal breaks at multiple locations and involves impaired DNA repair. In 2011, Stephens et al coined the term chromothripsis for this type of fragmenting event. Several proposed mechanisms have been suggested to underlie chromothripsis, such as p53 inactivation, micronuclei formation, abortive apoptosis and telomere fusions in telomere crisis. Chromothripsis gives rise to normal or abnormal phenotypes. In this review, constitutional chromothripsis, which may coexist with multiple de novo CNVs are described and discussed. This reviews aims to summarize recent advances in our understanding of CNVs and chromothripsis, and describe the effects of these phenomena on human health and birth defects.

The phenotype of 15 cases with rare 8q24.13‐q24.3 deletions–A new syndrome or still an enigma?

“…Demonstration of interstitial deletions with varying size and lack of uniform breakpoints raises the possibility of a one‐time phenomenon such as cytogenetic event (Bras et al, 2020). One of the clues supporting this hypothesis is recurrent miscarriage in one of our patients (case 7), and it is possible that the deletion was caused by an interstitial translocation in the gametes.…”

Mechanisms of structural chromosomal rearrangement formation

“…It was first described in cancer cells [ 60 ] and usually involves one chromosome, wholly or only one arm [ 28 , 59 , 61 ]. The formation of multiple clustered DSBs leads to local shattering, causing the chromosome to break into small fragments which are then randomly reassembled in a different order and orientation when compared to the original chromosome [ 28 , 59 , 61 – 63 ]. The whole process may happen inside a micronucleus, where missegregated chromosomes are encapsulated, pulverized, and then reassembled by c-NHEJ or MMEJ with the complex derivative chromosome reincorporated in the main nucleus [ 28 , 59 , 61 , 64 ].…”

“…The whole process may happen inside a micronucleus, where missegregated chromosomes are encapsulated, pulverized, and then reassembled by c-NHEJ or MMEJ with the complex derivative chromosome reincorporated in the main nucleus [ 28 , 59 , 61 , 64 ]. Deletions can be formed since some fragments may be lost if they are not incorporated in the process, but duplications are not found [ 28 , 61 – 63 ]. Distinguishable characteristics of chromothripsis include: (i) clustering of breakpoints showing signs of c-NHEJ or MMEJ, (ii) low DNA copy number changes with oscillation of copy number pattern between one (deleted fragments) and two copies, (iii) only one haplotype affected, and (iv) preservation of heterozygosity [ 59 , 61 , 62 , 65 ].…”

Distinct genomic features across cytolytic subgroups in skin melanoma

“…Local chromosome shattering (chromothripsis) is a mechanism proposed to cause clustered chromosomal rearrangements, following chromosomal breaks at multiple locations, and the criteria for its inference were previously described [36]. Chromothripsis has been detected in 2-3% of cancers and involves impaired DNA repair [37]. Such genomic rearrangements may drive the development of cancer through the deletion of tumor suppressor genes or an increase in copy number of oncogenes, among other mechanisms [38].…”